U.S. patent number 6,874,507 [Application Number 10/913,103] was granted by the patent office on 2005-04-05 for system for effecting smoking cessation.
This patent grant is currently assigned to Aradigm Corporation. Invention is credited to Stephen J. Farr.
United States Patent |
6,874,507 |
Farr |
April 5, 2005 |
System for effecting smoking cessation
Abstract
A system is disclosed which makes it possible for a patient to
be delivered gradually reduced amounts of nicotine over time
thereby allowing the patient to be gradually weaned off of
dependence on nicotine and quit smoking. The system is comprised of
a means for aerosolizing a formulation and containers of
formulation. The formulation is comprised of nicotine in a
pharmaceutically acceptable carrier. Preferably, a plurality of
containers are produced wherein the concentration of nicotine in
the different containers or different groups of containers is
reduced. The patient uses containers with the highest concentration
initially and gradually moves towards using containers with lower
and lower concentrations of nicotine until the patient's dependence
on nicotine is eliminated.
Inventors: |
Farr; Stephen J. (Orinda,
CA) |
Assignee: |
Aradigm Corporation (Hayward,
CA)
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Family
ID: |
29548312 |
Appl.
No.: |
10/913,103 |
Filed: |
August 6, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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147390 |
May 15, 2002 |
6799576 |
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611423 |
Jul 7, 2000 |
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Current U.S.
Class: |
131/271;
128/200.12; 128/200.14; 131/270; 131/328 |
Current CPC
Class: |
A61M
15/009 (20130101); A61M 16/10 (20130101); A61M
15/06 (20130101); A24F 42/20 (20200101); A61M
2209/06 (20130101) |
Current International
Class: |
A24F
47/00 (20060101); A61M 16/10 (20060101); A61M
15/00 (20060101); A61M 15/06 (20060101); A16M
016/00 () |
Field of
Search: |
;131/271,270,273,194,329,328
;128/202.21,200.12,200.14,200.13,203.15,203.12 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 99/15171 |
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Apr 1999 |
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WO |
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WO 99/45902 |
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Sep 1999 |
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WO |
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Other References
Clarke, (1992) "Nicotine dependence--mechanisms and therapeutic
strategies," Biochem. Soc. Symp., 59:83-95. .
Henningfield, (1995)"Nicotine Medications for Smoking Cessation,"
The New England Journal of Medicine, 333(18):1196-1203..
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Primary Examiner: Walls; Dionne A.
Attorney, Agent or Firm: Bozicevic; Karl Bozicevic, Field
& Francis LLP
Parent Case Text
CROSS-REFERENCE
This application is a divisional application of U.S. patent
application Ser. No. 10/147,390 filed May 15, 2002, now U.S. Pat.
No. 6,799,576, which is a continuation-in-part application of U.S.
patent application Ser. No. 09/611,423, filed Jul. 7, 2000 (now
abandoned) and claims the benefit of U.S. Provisional Application
No. 60/144,140, filed Jul. 16, 1999, which applications are
incorporated herein by reference.
Claims
What is claimed is:
1. A method of treatment, comprising the steps of: (a) providing a
system comprising: a device for creating aerosolized particles and
configured to receive a container containing a pharmaceutical
formulation to be aerosolized; a plurality of groups of containers
for use with the device, wherein each container within each group
of containers is comprised of a porous membrane with substantially
the same number and size of pores or pore sizes which is different
from each of the other groups of containers; (b) over a first
period of time, repeatedly using the device with a first group of
containers to aerosolize the pharmaceutical formulation; and (c)
over a second period of time, repeatedly using the device with a
second group of containers to aerosolize the pharmaceutical
formulation, wherein the number of pores or pore size in membranes
of the second group of containers is different from the number of
pores or pore sizes in the membranes of the first group of
containers.
2. The method of claim 1, further comprising: over any number of
subsequent periods of time, using the device with successive groups
of containers wherein the number of pores or pore sizes in the
subsequently used groups of containers is gradually changed with
each group of containers used.
3. The method of claim 1 wherein the number of pores or pore size
used during the first period of time is sufficient to produce an
arterial nicotine plasma concentration within the patient which
substantially corresponds to that achieved during cigarette
smoking.
4. The method of claim 1 wherein the particles have a size in the
range from about 0.5 to 12 .mu.m.
5. A method of treatment, comprising the steps of: (a) providing a
system comprising: a device for creating aerosolized particles and
configured to receive a container containing a pharmaceutical
formulation to be aersolized; a plurality of groups of containers
for use with the device, wherein each container within a group of
containers is comprised of a porous membrane with substantially the
same number of pores of substantially the same size and wherein
each group of containers is comprised of a membrane with a number
of pores or pore sizes different from each of the other groups of
containers; (b) using the device with a first container of a first
group of containers comprising a membrane with a first pore size
and pore number to aerosolize the pharmaceutical formulation; (c)
allowing the patient to inhale the aerosolized particles of (b)
thereby causing nicotine to directly enter the patient's arterial
system from the patient's lungs; (d) repeating steps (b) and (c)
once for any number of other containers of the first group of
containers; and (e) repeating step (d) for any number of other
groups of containers wherein the membrane pore size or pore number
in the subsequently used groups of containers is gradually
changed.
6. The method of claim 5 wherein the membrane pore size and number
used during the first occurrence of step (b) is sufficient to
produce an arterial nicotine plasma concentration within the
patient which substantially corresponds to that achieved during
cigarette smoking.
7. The method of claim 5 wherein the particles have a size in the
range from about 0.5 to 12 .mu.m.
8. A method of treatment, comprising the steps of: (a) providing a
system comprising: a device for creating aerosolized particles and
configured to receive a container containing a pharmaceutical
formulation to be aerosolized; a plurality of groups of containers
for use with the device, wherein each container within each group
of containers is comprised of substantially the same amount of
pharmaceutical formulation which amount of pharmaceutical
formulation is different from the amount of pharmaceutical
formulation in each of the other groups of containers; (b) over a
first period of time, repeatedly using the device with a first
group of containers to aerosolize the pharmaceutical formulation;
and (c) over a second period of time, repeatedly using the device
with a second group of containers to aerosolize the pharmaceutical
formulation, wherein the amount of pharmaceutical formulation in
the second group of containers is different from the amount of
pharmaceutical formulation in the first group of containers.
9. The method of claim 8, further comprising: over any number of
subsequent periods of time, using the device with successive groups
of containers wherein the amount of pharmaceutical formulation in
the subsequently used groups of containers is gradually changed
with respect to the amount of pharmaceutical formulation in each
other group of containers used.
10. The method of claim 8 wherein the amount of pharmaceutical
formulation aerosolized during the first period of time is
sufficient to produce an arterial nicotine plasma concentration
within the patient which substantially corresponds to that achieved
during cigarette smoking.
11. The method of claim 8 wherein the particles have a size in the
range from about 0.5 to 12 .mu.m.
12. The method of claim 8 wherein the pharmaceutical formulation is
a dry powder formulation.
13. The method of claim 12, further comprising: over any number of
subsequent periods of time, using the device with successive groups
of containers wherein the amount of dry powder formulation in the
subsequently used groups of containers is gradually changed with
respect to the amount of dry powder formulation in each other group
of containers used.
14. The method of claim 12 wherein the dry powder formulations in
the container is comprised of nicotine.
15. The method of claim 14, wherein the dry powder formulations are
comprised of particles with a particle size of from about 0.5 .mu.m
to about 2 .mu.m.
16. A method of treatment, comprising the steps of: (a) providing a
system comprising: a device for creating aerosolized particles and
configured to receive a container containing a pharmaceutical
formulation to be aerosolized; a plurality of groups of containers
for use with the device, wherein each container within a group of
containers is comprised of substantially the same amount of
pharmaceutical formulation wherein each group of containers is
comprised of an amount of pharmaceutical formulation different from
each of the other groups of containers; (b) using the device with a
first container of a first group of containers comprising a
membrane with a first amount of pharmaceutical formulation to
aerosolize the first amount of pharmaceutical formulation; (c)
allowing the patient to inhale the aerosolized particles of (b)
thereby causing nicotine to directly enter the patient's arterial
system from the patient's lungs; (d) repeating steps (b) and (c)
once for any number of other containers of the first group of
containers; and (e) repeating step (d) for any number of other
groups of containers wherein amounts of pharmaceutical formulation
in the subsequently used groups of containers is gradually changed
between the groups.
17. The method of claim 16 wherein the amounts of pharmaceutical
formulation aerosolized during the first occurrence of step (b) is
sufficient to produce an arterial nicotine plasma concentration
within the patient which substantially corresponds to that achieved
during cigarette smoking.
18. The method of claim 16 wherein the particles have a size in the
range from about 0.5 to 12 .mu.m.
Description
FIELD OF THE INVENTION
This invention relates generally to a method for treating
conditions responsive to nicotine therapy. More specifically, the
invention relates to pulmonary administration of nicotine to effect
smoking cessation.
BACKGROUND OF THE INVENTION
Diseases related to cigarette smoking, such as lung disease, heart
disease and cancer, claim an estimated 400,000 lives each year. The
combustion of tobacco produces poisons and carcinogens that present
a significant health hazard for smokers and non-smokers alike.
Nicotine is a principal component of tobacco, and the most
pharmacologically active. It is physically addictive, making it
extremely difficult for a smoker to quit.
Smoking a cigarette delivers nicotine vapors to the lungs, where
nicotine is rapidly absorbed through the arteries and delivered to
the brain. Nicotine interacts with nicotine cholinergic receptors
in the brain to induce the release of neurotransmitters and produce
an immediate reward--the "rush" that smokers experience--that is
associated with a rapid rise in blood level. A persistent stimulus
is also produced, and is associated with a high blood level of
nicotine. As such, the dopaminergic reward system is activated
which eventually results in nicotine dependency. Complex behavioral
and social aspects of smoking, e.g., the hand-to-mouth ritual,
etc., are also habit-forming.
A therapeutic approach to aid in smoking cessation is to provide
the smoker with nicotine from sources other than cigarettes.
Nicotine can be administered orally. However, after oral
administration it is absorbed from the gut into the portal blood
and degraded promptly by the liver. Nicotine can also be
administered parenterally, e.g., intravenously, transcutaneously,
muscosally, etc. Although preparations of nicotine appropriate for
intravenous administration have been available for some time,
intravenous cannulation as a means for gaining access to the
circulation for the administration of nicotine on demand is not a
socially acceptable alternative to cigarette smoking. There are
also a number of commercially available nicotine replacement
therapies that deliver nicotine to the systemic circulation via
absorption through mucosal membranes or the skin. These include
nicotine-containing chewing gum, sachets, transdermal patches,
capsules, tablets, lozenges, nasal sprays and oral inhalation
devices.
In particular, nicotine delivery via inhalation offers the benefit
of addressing the psychological component of cigarette smoking in
addition to the physiological dependence on nicotine. Nicotine
inhalation systems release nicotine as a vapor (see U.S. Pat. Nos.
5,167,242; 5,400,808; 5,501,236; 4,800,903; 4,284,089; 4,917,120;
4,793,366), aerosol (see U.S. Pat. Nos. 5,894,841; 5,834,011) or
dry powder (see U.S. Pat. No. 5,746,227) when air is inhaled
through the inhaler. A droplet ejection device (U.S. Pat. No.
5,894,841) has also been described that delivers a controlled dose
of nicotine via inhalation. These systems deliver low doses of
nicotine to the mouth and throat, where nicotine is absorbed
through the mucosal membranes into the circulation. Some inhalation
therapies feature devices that simulate or approximate the look,
feel and taste of cigarettes.
Currently available nicotine replacement therapies, such as
transdermal and buccal systems where absorption occurs slowly,
provide a low, steady-state blood level of nicotine to the patient
without the early nicotine concentration spike that occurs due to
immediate, arterial delivery of nicotine to the brain. Thus, the
goal of these therapies is to eliminate the immediate, pleasurable
effects associated with smoking while still alleviating the
nicotine withdrawal effects until complete cessation of nicotine is
physically and psychologically possible for the patient. The
perceived advantage of these therapies is that the likelihood of
abusing the nicotine delivery device (e.g., transdermal patch,
nicotine chewing gum, nicotine inhalers, etc.) is very low.
However, it is believed by some that it is because of this complete
lack of "rush" experienced by the patient, that the success rates
of these conventional therapies are not higher than they are.
Thus, the need remains for a smoking cessation therapy that
delivers a precise dose of nicotine directly to the lungs and,
therefore, directly into the arterial circulation in a profile that
mimics the blood levels achieved by cigarette smoking-providing an
initial sharp rise in blood level followed by a slow release of
nicotine-making it possible for the user to be weaned off of
nicotine and to quit smoking.
SUMMARY OF THE INVENTION
A system for aiding a patient in quitting smoking is disclosed. The
system is comprised of a means for the delivery of aerosolized
nicotine which makes it possible to gradually decrease the amount
of nicotine that the patient receives. The system comprises a means
for aerosolizing a formulation comprised of nicotine and a means
for decreasing the amount of nicotine formulation which is
aerosolized and/or the amount which actually reaches the patient's
circulatory system. The amount of nicotine aerosolized or
effectively delivered to the patient can be changed in several
different ways using either the device aerosolization mechanism,
the formulation or formulation containers loaded into the
device.
A preferred system of the invention aerosolizes the liquid
formulation by applying force to a container of nicotine
formulation and causing the nicotine formulation to be moved
through a porous membrane which results in creating particles of
nicotine formulation which are inhaled by the patient. This system
modifies the amount of nicotine aerosolized by providing a
plurality of different containers or different groups of containers
wherein the different containers or groups of containers contain
different concentrations of nicotine. A patient using the system
can utilize packets of nicotine formulation containing a high
concentration initially and then gradually switch towards lower and
lower concentrations so that the patient receives essentially the
same amount of aerosolized formulation but receives gradually
reduced amounts of nicotine due to the reduced concentration of the
nicotine in the formulation.
The same procedure described above can also be carried with a dry
powder inhaler (DPI). Using the dry powder inhaler technology the
packets of dry powder nicotine formulation loaded into the device
can initially contain a relatively high concentration of nicotine.
Thereafter, the concentration of nicotine in the dry powder
formulation added into the device is gradually decreased. Thus,
using this system the same amount of dry powder is aerosolized, but
the amount of nicotine is gradually decreased by decreasing the
concentration or simply the total amount of nicotine in the dry
powder package loaded into the device.
Additionally, the same procedure can be utilized with a
conventional metered dose inhaler (MDI) device. It is somewhat more
difficult to utilize the invention with an MDI device. However,
small pressurized canisters conventionally used with MDIs can
contain different concentrations of nicotine along with the
propellant. By using a first container which includes the highest
concentration of nicotine and gradually changing to lower and lower
concentrations of nicotine in the pressurized canister the desired
result of reducing the amount of nicotine delivered to the patient
can be obtained. The same results could be obtained by gradually
decreasing the amount of formulation released when the value of a
container is opened.
When using a dry powder inhaler or a system which aerosolizes a
liquid formulation by moving the formulation through a porous
membrane, it is possible to decrease the amount of nicotine
gradually by making changes in the device, or more specifically the
operation of the device. For example, a dry powder inhaler often
utilizes a burst of air in order to aerosolize the dry powder. The
burst of air could be decreased so that not all of the powder is
fully aerosolized or so that the powder is not aerosolized in a
completely efficient manner. In a more preferred embodiment the
system for aerosolizing liquid formulation is adjusted at different
points so that different amount of pressure are applied to the
formulation making it possible to aerosolize decreasing amounts of
formulation and allowing the patient to be gradually weaned off of
nicotine.
The most preferred embodiment of the invention involves the use of
a system which aerosolizes liquid formulations of nicotine
contained within individual packets which packets include a porous
membrane. As indicated above the amount of nicotine that can be
changed by changing the amount of or concentration of nicotine in
the packets. However, it is also possible to decrease the amount of
nicotine actually delivered to the patient's circulatory system by
changing the size of the pores in the membrane. When the pore size
is in a preferred range then a relatively high concentration of the
formulation aerosolized will reach the patient's lungs and move
from the lungs into the patient's circulatory system. However, by
making the pores larger the aerosolized particles created also
become larger. The larger particles will not move into the lungs as
efficiently as the smaller particles. Further, the larger particles
may be deposited in areas where they are not readily absorbed into
the patient's circulatory system.
Thus, in accordance with a preferred embodiment of the invention, a
plurality of different containers are produced. The containers are
different from each other in that they contain different amounts or
concentrations of nicotine. Alternatively, the containers are
different from each other in that they have different porous
membranes on them which make it possible to aerosolize the
formulation in a somewhat less efficient manner over time. It is
possible to combine both or all three features together. More
specifically, it is possible to produce containers which contain
(1) smaller concentrations of nicotine; (2) smaller amounts of
nicotine; or (3) have porous membranes which have different size or
amounts of pores so as to less efficiently aerosolize the
formulation present in the container.
A method for aiding in smoking cessation and for treating
conditions responsive to nicotine therapy by the administration of
nicotine is disclosed. A formulation comprised of nicotine is
aerosolized. The aerosol is inhaled into the lungs of the patient.
Once inhaled, particles of nicotine deposit on lung tissue and,
from there, enter the patient's circulatory system. Because
delivery is to the lungs, rather than to the oral mucosa or through
the skin, the nicotine is immediately delivered, along with freshly
oxygenated blood, to the heart via the pulmonary arteries where it
is then pumped via the aorta to the arterial circulatory system,
which is responsible for the delivery of oxygenated blood to the
patient's entire body. The carotid arteries, in particular,
transport the nicotine-containing oxygenated blood directly to the
brain where it is then perfused throughout the brain by the
neurovasculature system. Thus, the patient's serum nicotine level
in the brain is quickly raised to a desired level--as quickly as if
the user were smoking, providing the "rush" effect. The smoker
isn't immediately deprived of the psychological pleasures of
smoking and, as such, is more likely to successfully complete the
smoking-cessation treatment. Because the methods of the invention
substantially bypass the body's processes that would effectively
metabolize (e.g., by the liver) or dilute (e.g., by systemic
distribution via the venous circulatory system) the nicotine dose
and thus minimize the effect of the nicotine dose prior to delivery
to the brain, the inventive methodologies are able to produce
arterial plasma concentrations of nicotine similar to those
experienced during cigarette smoking.
Subsequently, the patient's dependence on nicotine is reduced by
gradually reducing the dose of nicotine. The dose of nicotine is
reduced by progressively increasing the size distribution of the
aerosolized nicotine particles delivered to the patient. This
decreases the amount of nicotine delivered to the patient's lungs,
with the result that nicotine absorption is less immediate and the
nicotine blood plasma level is lower.
A method of treatment is disclosed, comprising:
(a) aerosolizing a formulation comprised of nicotine creating
aerosolized articles which are sufficiently small as to enter the
alveolar ducts;
(b) allowing a patient to inhale the aerosolized particles of (a)
thereby causing nicotine to enter the patient's blood at air/blood
diffusion membranes;
(c) repeating (a) and (b) a plurality of times;
(d) aerosolizing a formulation comprised of nicotine creating
aerosolized particles which are too large to enter alveolar ducts
but sufficiently small to enter primary and secondary
bronchioles;
(e) allowing the patient to inhale the aerosolized particles of (d)
into primary and secondary bronchioles; and
(f) repeating (d) and (e) a plurality of times.
The method is preferably further comprised of:
(g) aerosolizing a formulation comprised of nicotine creating
aerosolized particles which are too large to enter primary and
secondary bronchioles but sufficiently small to enter the small
bronchi;
(h) allowing the patient to inhale the aerosolized particles of (g)
into small bronchi; and
(i) repeating (g) and (h) a plurality of times.
Another method of treatment is disclosed which includes the steps
of:
(a) aerosolizing a pharmaceutical formulation comprised of nicotine
to create aerosolized particles having a size in the range from
about 0.5 to 12.mu.; and
(b) allowing the patient to inhale the aerosolized particles of (a)
thereby causing nicotine to directly enter the patient's arterial
system from the patient's lungs.
The method may further include the step of:
(c) repeating steps (a) and (b) a plurality of times.
In certain embodiments, this method may further include the steps
of:
(d) performing step (c) over a first period of time wherein the
nicotine is present in a first concentration; and
(e) performing step (c) over a second period of time wherein the
nicotine is present in a second concentration which is less than
the first concentration.
In other embodiments, this method may further include the steps
of:
(d) performing step (c) over a first period of time wherein the
aerosolized particles have a first size; and
(e) performing step (c) over a second period of time wherein the
aerosolized particles have a second size which is greater than the
first size.
An aspect of the invention is a method of treatment whereby
nicotine or a nicotine substitute is aerosolized, inhaled into
areas of the respiratory tract including the lungs and provided to
the arterial circulatory system of the patient at levels sufficient
to simulate cigarette smoking.
An advantage of the invention is that the nicotine levels are
raised almost immediately on administration.
Another advantage of the invention is that the patient can
gradually be weaned off of the immediate effect of nicotine
obtained via smoking and gradually weaned off of the need of
nicotine by, respectively, increasing particle size and decreasing
dose size or concentration.
A feature of the invention is that aerosolized particles of
nicotine having a diameter of about 0.5 to 8 microns (.mu.) are
created and inhaled deeply into the lungs, thereby enhancing the
speed and efficiency of administration.
It is an object of this invention to describe the utility of
delivering nicotine by inhalation as a means of treating conditions
responsive to nicotine therapy, and particularly for smoking
cessation therapy.
It is another object of this invention to describe the utility of
varying the distribution of aerosolized particles of nicotine
inhaled as a means of treating smokers wishing to quit.
It is another object of this invention to describe liquid
formulations (which includes suspensions) of nicotine and
derivatives thereof appropriate for pulmonary delivery.
It is another object of this invention to describe how nicotine
delivered via the lung can quickly increase arterial nicotine blood
plasma concentration levels.
An aspect of the invention is a method whereby larger and larger
particles of aerosolized nicotine are administered to a patient
over time in order to first wean a smoking patient off of the
addiction to the immediate effects of nicotine and, thereafter,
reduce the amount of nicotine in order to wean the patient
completely off of the addiction to nicotine, thereby allowing the
patient to quit smoking.
A feature of this invention is that it allows for the formation of
nicotine particles in different sizes designed for delivery to
different areas of a patient's lungs.
An advantage of the invention is that it allows the patient to be
weaned off of (1) the need for immediate nicotine delivery as
obtained when smoking, and (2) the need for nicotine at all.
These and other aspects, objects, advantages, and features of the
invention will become apparent to those skilled in the art upon
reading this disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic view of a human lung branching pattern.
FIG. 2 is a schematic view of a human respiratory tract.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Before the devices, formulations, and methodology of the present
invention are described, it is to be understood that this invention
is not limited to the particular device, components, formulations
and methodology described, as such may, of course, vary. It is also
to be understood that the terminology used herein is with the
purpose of describing particular embodiments only, and is not
intended to limit the scope of the present invention which will be
limited only by the appended claims.
It must be noted that as used herein and in the appended claims,
the singular forms "a," "and," and "the" include plural referents
unless the context clearly dictates otherwise. Thus, for example,
reference to "a formulation" includes mixtures of different
formulations and reference to "the method of treatment" includes
reference to equivalent steps and methods known to those skilled in
the art, and so forth.
Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the invention, the
preferred methods and materials are now described. All publications
mentioned herein are incorporated herein by reference to describe
and disclose specific information for which the reference was cited
in connection with.
Defenitions
The term "nicotine" is intended to mean the naturally occurring
alkaloid known as nicotine, having the chemical name
S-3-(1-methyl-2-pyrrolidinyl)pyridine, which may be isolated and
purified from nature or synthetically produced in any manner. This
term is also intended to encompass the commonly occurring salts
containing pharmacologically acceptable anions, such as
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or
bisulfate, phosphate or acid phosphate, acetate, lactate, citrate
or acid citrate, tartrate or bitartrate, succinate, maleate,
fumarate, gluconate, saccharate, benzoate, methanesulfonate,
ethanesulfonate, benzenesulfonate, p-toluene sulfonate, camphorate
and pamoate salts. Nicotine is a colorless to pale yellow, strongly
alkaline, oily, volatile, hygroscopic liquid having a molecular
weight of 162.23 and the formula: ##STR1##
Structure and ionisation of nicotine. Nicotine is approximately 10%
of the particulate weight in cigarette smoke. Brand differences
change this percentage. It is monoprotonated at most physiological
pH values. The diprotonated ion would exist at pH values found in
the stomach. Metabolism is largely due to oxidation. Cotinine is a
major metabolite; however, there are at least 4 primary metabolites
of nicotine and all are encompassed by the use of this term
herein.
The term "nicotine" further includes any pharmacologically
acceptable derivative, metabolite or analog of nicotine which
exhibits pharmacotherapeutic properties similar to nicotine. Such
derivatives and metabolites are known in the art, and include
cotinine, norcotinine, nornicotine, nicotine N-oxide, cotinine
N-oxide, 3-hydroxycotinine and 5-hydroxycotinine or
pharmaceutically acceptable salts thereof. A number of useful
derivatives of nicotine are disclosed within the Physician's Desk
Reference (most recent edition) as well as Harrison's Principles of
Internal Medicine. In addition, applicants refer to U.S. Pat. Nos.
5,776,957; 4,965,074; 5,278,176; 5,276,043; 5,227,391; 5,214,060;
5,242,934; 5,223,497; 5,278,045; 5,232,933; 5,138,062; 4,966,916;
4,442,292; 4,321,387; 5,069,094; 5,721,257; all of which are
incorporated herein by reference to disclose and describe nicotine
derivatives and formulations.
The physiologically active form of nicotine is the S-(--)-isomer.
Certain compounds of the present invention may exist in particular
geometric or stereoisomeric forms. The present invention
contemplates all such compounds, including cis and trans isomers, R
and S enantiomers, diastereomers, the racemic mixtures thereof, and
other mixtures thereof, as falling within the scope of the
invention. Additional asymmetric carbon atoms may be present in a
substituent such as an alkyl group. All such isomers, as well as
mixtures thereof, are intended to be included in this
invention.
The term "upper airways" and the like are used interchangeably
herein to define an area of the respiratory system which includes
the oropharyngeal region and trachea. This area is the first area
which air enters upon inhalation (see FIG. 1).
The terms "central airways," "bronchial airways" and the like are
used interchangeably herein to refer to a region of the respiratory
system that includes generations 1 through 16 of the airways (see
FIG. 1) which removes particles larger than 3.mu.in diameter. They
are the conductive airways that also clean particles from the lung
using a mucosal clearance mechanism. Upon inhalation, air passes
through the upper airways into the central airways.
The terms "pulmonary region," "peripheral region" and the like are
used interchangeably herein to define a region of the respiratory
system where gas exchange occurs between the lungs and the
circulatory system, i.e., where oxygen enters the blood and carbon
dioxide leaves the blood. The peripheral region includes
generations 17 through 23 of the airways (see FIG. 1). Drugs
delivered to this area generally have a systemic effect.
The terms "alveolar ducts," "alveoli" and the like refer to
components in the pulmonary region of the lung which are
approximately 3.mu.in diameter where gas change occurs between the
air in the lungs and the circulatory system.
The term "diameter" is used herein to refer to particle size as
given in the "aerodynamic" size of the particle. The aerodynamic
diameter is a measurement of a particle of unit density that has
the same terminal sedimentation velocity in air under normal
atmospheric conditions as the particle in question. This is pointed
out in that it is difficult to accurately measure the diameter of
small particles using current technology and the shape of such
small particles may be continually changing. Thus, the diameter of
one particle of material of a given density will be said to have
the same diameter as another particle of the same material if the
two particles have the same terminal sedimentation velocity in air
under the same conditions. In connection with the present
invention, it is important that particles, on average, have the
desired diameter so that the particles can be inhaled and targeted
to a specific area of the lungs. It is also important not to have
particles which are too small in that such particles would be
inhaled into the lungs and then exhaled without depositing on the
lung tissue in the same manner that particles of smoke can be
inhaled and exhaled with only a small amount of the particles being
deposited on the lung tissue. An acceptable range for particle
diameter varies depending on the area of the respiratory tract
being targeted. To target the alveolar ducts and alveoli the
particles should have a diameter in a range of about 0.5.mu. to
about 2.mu.. To target the area above the alveolar ducts and below
the small bronchi the diameter should be in the range of from about
2.mu. to about 4.mu., and to target the small bronchi and above the
particles should have a diameter of from about 4.mu. to about
8.mu..
The term "porous membrane" shall be interpreted to mean a membrane
of material in the shape of a sheet having any given outer
perimeter shape, but preferably covering a package opening which is
in the form of an elongated rectangle, wherein the sheet has a
plurality of openings therein, which openings may be placed in a
regular or irregular pattern, and which openings have a diameter in
the range of 0.25.mu. to 4.mu. and a pore density in the range of
1.times.10.sup.4 to about 1.times.10.sup.8 pores per square
centimeter. Alternatively, the porous membrane may be merely an
area of the package which has pores therein wherein the pores have
a size and a density as described above. The configuration and
arrangement of the pore density may be changed so as to provide
pores which are capable of creating the desired amount of aerosol.
For example, the porous membrane or area of the container may have
some 10 to 10,000 pores therein which pores are positioned in an
area of from about 1 mm.sup.2 to about 1 cm.sup.2. The membrane is
preferably comprised of a material having a density in the range of
0.25 to 3.0 mg/cm.sup.2, more preferably 1.7 mg/cm.sup.2, and a
thickness of about 2.mu. to 20.mu., more preferably about 8.mu.; to
12.mu.. The membrane material is preferably hydrophobic and
includes materials such as polycarbonates and polyesters which may
have the pores formed therein by any suitable method including
anisotropic etching or by etching through a thin film of metal or
other suitable material. Pores can be created in the membrane which
may be an area of the container by use of techniques such as
etching, plating or laser drilling. The membrane materials may have
pores with a conical configuration and have sufficient structural
integrity so that it is maintained intact (will not rupture) when
subjected to force in the amount of about 20 to 200 psi while the
formulation is forced through the pores. The membrane functions to
form an aerosolized mist when the formulation is forced through it.
Those skilled in the art may contemplate other materials which
achieve this function as such materials are intended to be
encompassed by this invention.
The terms "treatment," "treating," and the like are used
interchangeably herein to generally mean obtaining a desired
pharmacological and/or physiological effect. The terms are used in
a manner somewhat differently than the terms are typically used in
that what is intended by the method of treatment of the invention
is to allow a patient to overcome an addiction to nicotine and
thereby allow the patient to quit smoking. The treating effect of
the invention provides a psychological effect in that the invention
originally delivers high doses of nicotine in a manner that
simulates the nicotine delivery obtained from a cigarette. The
patient then becomes accustomed to relying on the methodology of
the invention to provide an immediate "rush" of nicotine.
Thereafter, the particles of the aerosol are made larger. This
prevents the particles from penetrating deeply into the lung and,
therefore, to some extent, diminishes the "rush" of nicotine.
However, the same amount of nicotine is still given to the patient
in order to satisfy the overall nicotine craving. Eventually, the
treatment of the invention reduces the amount of nicotine so as to
allow the patient to completely "wean" off of nicotine and to quit
smoking.
All publications mentioned herein are incorporated herein by
reference to described and disclose specific information for which
the reference was cited in connection with. The publications
discussed herein are provided solely for their stated disclosure
prior to the filing date of the present application. Nothing herein
is to be construed as an admission that the invention is not
entitled to antedate such publications by virtue of prior
invention. Further, the actual publication date may be different
from that stated on the publication and as such may require
independent verification of the actual publication dates.
General Methodology
The steady state delivery of nicotine as therapy for smokers
wishing to quit is characterized by slow absorption and low blood
levels of nicotine, which limits its utility. The present invention
replaces the nicotine that a smoker receives from smoking a
cigarette in a therapeutically effective manner by providing a
rapid pulse of bioavailable nicotine to the smoker on demand. More
specifically, the present invention provides a treatment
methodology wherein a patient's arterial nicotine plasma
concentration over a selected time, i.e., the arterial nicotine
plasma concentration-rate profile, substantially correlates to that
of the patient when smoking a cigarette.
One means currently available for a true pulsatile, rapid onset
replacement therapy is intravenous administration. Although
preparations of nicotine appropriate for intravenous administration
have been available for some time, intravenous cannulation as a
means for gaining access to the circulation for the administration
of nicotine on demand is not a socially acceptable alternative to
cigarette smoking.
The treatment methodology of the present invention creates an
aerosol of nicotine particles. The nicotine particles may be formed
from any liquid containing nicotine including a solution or
suspension of nicotine and aerosolized in any known manner
including (1) moving the formulation through a porous membrane in
order to create particles or (2) a dry powder where the particles
of powder have been designed to have a desired diameter. The rate
of particle absorption is directly proportional to the surface area
of the tissue on which the particles are deposited. Accordingly,
nicotine is absorbed more slowly through the mucosal membranes of
the upper respiratory tract which have a smaller surface area than
through the airways in the lower respiratory tract which have a
larger surface area. Thus, the overall effect of increasing the
size of the nicotine particles is to reduce the rate at which
nicotine is absorbed into the circulation, thereby reducing the
smoker's physiological dependence on the quick rush of nicotine
experienced when smoking.
Method of Treatment
The penetration of aerosolized nicotine particles into the
respiratory tract is determined largely by the size distribution of
the particles formed. Larger particles, i.e., particles with a
diameter .gtoreq.5.mu., deposit on the upper airways of the lungs
(see FIG. 1). Particles having a diameter in a range of about
>2.mu., to <5.mu. penetrate to the central airways. Smaller
particles having a diameter .gtoreq.2.mu. penetrate to the
peripheral region of the lungs.
An important feature of the invention is that the treatment
methodology begins with particles of a given size, carries out
treatment for a given period of time after which the particles are
increased in size. The particles initially administered to the
patient penetrate deeply into the lung, i.e., the smallest
particles (e.g., 0.5 to 2.mu.) target the alveolar ducts and the
alveoli. When the deepest part of the lung is targeted with the
smallest particles the patient receives an immediate "rush" from
the nicotine delivered which closely matches that received when
smoking a cigarette. These small particles can be obtained by
milling powder into the desired size and inhaling the powder or by
creating a solution or suspension and moving the solution or
suspension through the pores of a membrane. In either case, the
desired result is to obtain particles which have a diameter in the
range of 0.5.mu. to about 2.mu.. Those skilled in the art will
understand that some of the particles will fall above and below the
desired range. However, if the majority of the particles (50% or
more) fall within the desired range then the desired area of the
lung will be correctly targeted.
The patient is allowed to continually, from time to time, target
the outermost area of the lung with the smallest particles. For
example, the patient would be instructed to repeatedly administer
the smallest size particles when the patient would normally smoke a
cigarette. In this manner, the patient will become accustomed to
finding that the device administers nicotine into the patient in
the same manner that a cigarette does. In one embodiment of the
invention the concentration of the nicotine in the liquid
formulation could be reduced gradually over time. This could be
done over a sufficiently long period of time so as to allow the
patient to "wean" off of nicotine. However, in a more preferred
embodiment of the invention the amount of nicotine is kept
substantially constant but the size of the aerosolized particles
created are increased.
The second phase of the treatment methodology is to increase the
size of the particles so as to target the respiratory tract above
the alveolar ducts and below the small bronchi. This can generally
be accomplished by creating aerosolized particles of nicotine which
have a size and range of about 2.mu. to about 4.mu.. Administration
is carried out in the same manner as described above. Specifically,
the patient administers the aerosolized nicotine at the same time
when the patient would be smoking a cigarette. Since the patient
has become adjusted to receiving the nicotine "rush" from the
smaller sized particles, the patient will expect and is therefore
likely to experience the same "rush" when administering the
slightly larger particles. However, the effect will be less
immediate. This procedure is carried out over a period of time,
e.g., days or weeks. In one embodiment of the invention it is
possible to reduce the dose of aerosolized nicotine delivered to
the patient during this second phase. However, the dose may remain
constant.
The treatment can be completed after any phase, e.g. after the
second phase. However, in accordance with a more preferred
embodiment of the invention a third phase of treatment is carried
out. Within the third phase the particle size of the aerosolized
nicotine is increased again. The particles are increased to a size
in a range from about 4.mu. to about 8.mu. or, alternatively,
perhaps as large as 12.mu.. These larger particles will target the
upper airways. The larger particles will give a very small
immediate "rush" but will still be absorbed through the mucous
membranes of the patient's respiratory tract. Accordingly, the
patient will be administering nicotine doses which may be the same
as those doses administered at the beginning of treatment. At this
point the treatment can take a number of different directions. The
patient can attempt to stop administration by immediate and
complete cessation of nicotine delivery. Alternatively, the patient
can try to wean off of nicotine by delivering fewer doses during a
given time period. In another alternative, the same size dose
(volume of aerosol formulation) is administered and delivered,
creating the same amount of aerosol, but wherein the aerosolized
particles contain progressively less nicotine (i.e., more dilute
concentration). The amount of nicotine can be decreased until the
patient is receiving little or no nicotine. Those skilled in the
art reading this disclosure will recognize variations on the
overall method and methods for stopping treatment.
There are a number of aspects of the invention which will result in
the ability of the smoker to use the invention and, eventually,
quit smoking. Firstly, the invention is particularly suited for
smokers in that smokers are accustomed to inhaling their source of
nicotine. Other treatments such as those involving the transdermal
delivery of nicotine via a nicotine "patch" or buckle delivery via
a nicotine "gum" do not match the means which a smoker usually
obtains nicotine.
Further, the present invention provides a method wherein the
patient obtains an influx of nicotine into the circulatory system
at a rate which substantially matches the rate which nicotine would
enter the circulatory system when smoking. This is obtained
because, at least at first, the invention provides sufficiently
small particles such that they are inhaled deeply into the lung,
i.e. 50% or more of the particles are inhaled deeply into the lung
and thereby quickly enter the patient's circulatory system.
Thirdly, the present invention is advantageous in that the rate at
which the delivered nicotine enters the circulatory system can be
gradually decreased by gradually increasing the size of the
aerosolized particles delivered to the patient. This can be done
over any desired period of time and in any desired number of
phases.
Lastly, the invention provides a means whereby the amount of
nicotine delivered to the patient can be gradually decreased in a
number of different ways. Firstly, it can be decreased by
decreasing the concentration of nicotine in the aerosolized
formulation. Secondly, it can be decreased by merely decreasing the
number of administrations of aerosolized doses. Thirdly, it can be
decreased by decreasing the size of the dose aerosolized and
inhaled by the patient. one aspect of the invention is a method of
treatment, comprising:
(a) aerosolizing a formulation comprised of nicotine creating
aerosolized particles which are sufficiently small to target a
particular lower area of the respiratory tract such as the alveoli.
The particles targeting this area will have a relatively small
size, e.g. 0.5 micron to about 2 microns in diameter.
(b) in the next step the patient inhales the aerosolized particles
of (a) into the respiratory tract, preferably targeted to a
specific area of the lower respiratory tract there the deposited
particles cross into the patient's circulatory system.
In step (c), steps (a) and (b) are repeated a plurality of times.
Specifically, the patient may repeat these steps any number of
times such as every time the patient would normally smoke a
cigarette. At this point the patient could continue the treatment
protocol in this manner and gradually decrease the number of times
the patient administers aerosolized nicotine until the patient is
no longer addicted to nicotine. Decreasing the amount of
aerosolized nicotine could also be done by decreasing the
concentration of nicotine within the aerosolized particles
decreasing the concentration of nicotine in the formulation and/or
decreasing the size of the aerosolized dose.
Preferably the method of the invention continues with a step (d)
which involves aerosolizing formulation comprised of nicotine in
order to create aerosolized particles which are larger in size than
the aerosolized particles produced in step (a). These larger
particles are directed towards a particular area of the patient's
respiratory tract, e.g. the mid-region of the patient's respiratory
tract. (See FIGS. 1 and 2) These particles could have a size in the
range of about 2 microns to about 4 microns.
In the following step (d) the patient inhales the aerosolized
particles of (d) thereby targeting the particular desired area of
the patient's respiratory tract such as the mid region. Thereafter,
steps (d) and (e) are repeated a plurality of times. At this point
the patient can decrease the amount of nicotine being delivered as
indicated in the same manner as indicated above step (c).
Alternatively, the method of the invention can be continued so that
a third phase of treatment can be carried out which phase is
similar to the two phases described above. In accordance with the
above invention it is possible to carry out the treatment in any
number of phases. For example, the treatment could involve as many
as 24 phases which target specific defined regions of a patients
respiratory tract using particles which are continually larger in
size in each of the 24 phases (see FIG. 1 and Table 1 below).
Because it may not be practical to specifically design the
particles so that they are all larger in each of the phases the
formulations may be designed so that a certain percentage of the
particles within each phase of delivery is larger than the
particles in the preceding phase.
The method of the invention can be carried out using 1 to 24
different phases with each phase targeting a higher level of the
respiratory tract (See Table 1). The higher levels of the
respiratory tract can be targeted using larger and larger
particles.
TABLE 1 Subdivision of the Respiratory Tree Generation Name 0
Trachea 1 Primary bronchi 2 Lobar bronchi 3 Segmental bronchi 4
subsegmental bronchi 5 Small bronchi .dwnarw. 10 11 Bronchioles,
primary and secondary .dwnarw. 13 14 Terminal bronchioles .dwnarw.
15 16 Respiratory bronchioles .dwnarw. 18 19 Alveolar ducts
.dwnarw. 23 24 Alveoli
Nicotine Delivery Devices
Precision delivery of small molecule drugs via the lung for
systemic effect is possible. An electronic inhaler capable of
delivering a liquid formulated drug stored in a unit dose packages
has been described and disclosed in U.S. Pat. No. 5,718,222
entitled "Disposable Package for Use in Aerosblized Delivery of
Drugs," and is incorporated herein by reference. A formulation of
nicotine can be prepared for delivery with this system.
Quantitative delivery of nicotine on demand provides a mechanism
for nicotine replacement therapy which is unlikely to be associated
with recidivism precipitated by the symptoms of physical
withdrawal.
In the present invention, a nicotine formulation is forced through
the openings or pores of a porus embrane to create an aerosol. In
the preferred embodiment, the openings are all uniform in size and
are positioned at uniform distances from each other. However the
openings can be varied in size and randomly placed on the membrane.
If the size of the openings is varied, the size of the particles
formed will also vary. In general, it is preferable to maintain
uniform opening sizes in order to create uniform particles sizes,
and it is particularly preferable to have the opening sizes within
the range of about 0.25.mu. to about 6.mu. which will create
particle sizes of about 0.5.mu. to 12.mu. which are preferred with
respect to inhalation applications. When the openings have a pore
size in the range of 0.25.mu. to 1.mu. they will produce an aerosol
having particle sizes in the range of 0.5.mu. to 2.mu., which is
particularly useful for delivering nicotine to the alveolar ducts
and alveoli. Pore sizes having a diameter of about 1.mu. to 2.mu.
will produce particles having a diameter of about 2.mu. to 4.mu.,
which are particularly useful for delivering nicotine to the area
above the alveolar ducts and below the small bronchi. A pore size
of 2.mu. to 4.mu. will create particles having a diameter of of
4.mu. to 8.mu. which will target the area of the respiratory tract
from the small bronchi upward.
Increasing the size of the openings of the porous membranes
produces nicotine particles of increasing size. A strategy in which
the blood level of nicotine is reduced gradually will be the most
effective in treating the symptoms of withdrawal, and thereby
increase the chances of successful smoking cessation. In one
embodiment of the invention, the size of the aerosolized nicotine
particles is increased in a stepwise manner by using porous
membranes that create "monodisperse" aerosols, wherein all the
particles within the aerosol created have essentially the same
particle size. Nicotine particles of increasing size are produced
by using membranes of increasing pore sizes.
In another embodiment, the size of the aerosolized nicotine
particles is increased in gradient fashion by using porous
membranes that create "multi-disperse" aerosols, wherein the
particles within the aerosol created have different particle sizes.
Membranes which have an increasing range of pore sizes are used to
produce nicotine particles of increasing size.
Nicotine can be administered orally. However, after oral
administration it is absorbed from the gut into the portal blood
and degraded promptly by the liver. Thus, insignificant amounts
reach the patient's systemic circulation. Nicotine can also be
administered parenterally. However, when so administered it is
rapidly absorbed and metabolized making it difficult to sustain
therapeutic levels in plasma over time. In view of such, effective
therapy has been carried out using other means of delivery (e.g.,
transdermal patches, gum). The present invention uses
intrapulmonary delivery to avoid first pass liver metabolism and to
obtain quick infusion into the arterial side of the patient's
systemic circulatory system. The present invention administers
sufficient nicotine by inhalation to temporarily produce a rapid
increase in the patient's blood level, and thereafter allow the
patient's nicotine level to return to a therapeutically effective
level.
Because intrapulmonary administration is not 100% efficient, the
amount of drug aerosolized will be greater than the amount that
actually reaches the patient's circulation. For example, if the
inhalation system used is only 50% efficient then the patient will
aerosolize a dose which is twice that needed to raise the patient's
nicotine level to the extent needed to obtain the desired results.
More specifically, when attempting to administer 1 mg of nicotine
with a delivery system known to be 50% efficient, the patient will
aerosolize an amount of formulation containing about 2 mg of
nicotine.
A device comprised of a container that includes an opening covered
by a porous membrane, such as the device disclosed in U.S. Pat. No.
5,906,202, may be used to deliver nicotine. The device may be
designed to have the shape and/or bear the markings of a pack of
cigarettes, and may include the scent of tobacco. These features
and others that address the behavioral component of cigarette
smoking may enhance the effectiveness of the method described
herein.
Dosing
Cigarettes contain 6 to 11 mg of nicotine, of which the smoker
typically absorbs 1-3 mg; see Henningfield N Engl J Med
333:1196-1203 (1995). Factors influencing nicotine absorption
include subject-dependent factors, such as smoking behavior, lung
clearance rate, etc., morphological factors, and physiological
factors, such as tidal volume, inspiratory and expiratory flow
rate, particle size and density.
See Darby et al., Clin Pharmacokinet 9:435-439 (1984). The systemic
dose of nicotine per puff is extremely variable, however, peak
plasma concentrations of 25-40 ng/mL of nicotine, achieved within
5-7 minutes by cigarette smoking, are believed typical. In
accordance with the present invention, 0.1 mg to 10 mg, preferably
1 to 3 mg, and more preferably about 2 mg of nicotine are delivered
to the lungs of the patient in a single dose to achieve peak blood
plasma concentrations of 15-40 ng/mL.
The amount of a nicotine administered will vary based on factors
such as the age, weight and frequency of smoking or nicotine
tolerance of the smoker. Other factors, such as daily stress
patterns, demographic factors may also determine, in part, the
amount of nicotine sufficient to satisfy the smoker's craving for
nicotine. Administering nicotine using the methods of the present
invention can involve the daily administration of anywhere from 5
mg to 200 mg of nicotine, but more preferably involves the
administration of approximately 10 to 100 mg per day.
It is noted that nicotine can be administered in toxic amounts.
Care should be taken not to overdose the patient. The amount of
nicotine which an individual can tolerate will vary on a number of
factors including size, sex, weight and amount of cigarette smoking
the patient is accustomed to. In order to avoid overdosing it is
possible to program a lock-out system into the delivery device
which prevents administration of aerosolized doses beyond a given
point. Such a system is described within U.S. Pat. No. 5,735,263
issued Apr. 7, 1998 and incorporated herein by reference in its
entirety to disclose drug delivery devices and lock-out systems
used in connection therewith.
The nicotine is in a liquid form or is dissolved or dispersed
within a pharmaceutically acceptable, liquid excipient material to
provide a liquid, flowable formulation which can be readily
aerosolized. The container will include the formulation having
nicotine therein in an amount of about 10 mL to 300 mL, more
preferably about 200 mL. The large variation in the amounts which
might be delivered is due to different delivery efficiencies for
different devices. Administration may involve several inhalations
by the patient, with each inhalation providing nicotine from the
device. For example, the device can be programmed so as to release
the contents of a single container or to move from one container to
the next on a package of interconnected containers. Delivering
smaller amounts from several containers can have advantages. Since
only small amounts are delivered from each container and with each
inhalation, even a complete failure to deliver nicotine with a
given inhalation is not of great significance and will not
seriously disturb the reproducibility of the dosing event. Further,
since relatively small amounts are delivered with each inhalation,
the patient can safely administer a few additional micrograms (or
milligrams) of nicotine without fear of overdosing.
In one embodiment of the invention the patient is treated in the
three different phases. In the first phase the aerosolized liquid
particles or dry powder particles have a size and a range of
0.5.mu. to about 2.mu.. The particles of nicotine having this size
are administered in a dosage amount which is substantially
equivalent to the doses or amount which the patient would received
from a single cigarette or, alternatively, the dosage amount which
the patient would received from a single puff on a single
cigarette. Assuming that the patient receives the dosage amount of
a single cigarette then the patient will be administered
approximately 1 to 3 mg of nicotine each time the formulation is
aerosolized. The particles having a size of 0.5.mu. to about 2.mu.
will be administered to the patient over a plurality of days (e.g.,
2 to 7 days) or perhaps a plurality of weeks (e.g., 2 to 4 weeks).
If the device and/or dosage containers are designed to deliver a
dosage equivalent to a puff on a cigarette then substantially
smaller doses are delivered. If each dose corresponds to a puff on
a cigarette then a patient may be directed to continually take
aerosolized doses equivalent to a cigarette puff over a period of
one to ten minutes or any period of time equivalent to what that
patient normally takes to smoke one cigarette. This constitutes the
first phase of treatment.
After completing the first phase of the treatment the method of the
invention may be completed. However, as indicated above the method
may be continued by repeating phases such as the first phase using
continually larger particles and/or continuing more dilute
solutions of nicotine and/or smaller doses of nicotine.
Within the second phase of treatment the patient is preferably
administered the same dosage amount of nicotine with each
inhalation, e.g., the patient is administered 1 to 3 mg of nicotine
each time formulation is aerosolized. However, during the second
phase the size of the particles is increased to a size and range
from 2.mu. to about 4.mu.. The particle size is increased in order
to target an area of the lungs where the nicotine will be absorbed
into the circulatory system more slowly. Specifically, the larger
particles target an area of the lungs above the alveolar ducts and
below the small bronchi. Administration is carried out over a
plurality of days or a plurality of weeks in the same manner as
indicated above. Within all phases the patient preferably
administers nicotine from a device of the invention when the
patient would normally smoke a cigarette. The treatment can be
completed pursuant to the present invention by using only the two
phases. However, it is preferable to include three or more
phases.
In accordance with the third phase, the same dose is administered
each time nicotine formulation is aerosolized. Accordingly, 1 to 3
mg of nicotine is delivered to the patient at each dose. However,
the dose is delivered by using aerosolized particles which have a
diameter of 4.mu. or more, e.g., in the range of from 4.mu. to
about 8.mu.. These larger particles are designed to target the area
of the respiratory tract at the small bronchi or higher. When the
nicotine targets the upper airways it will not immediately enter
the patient's circulatory system. However, the nicotine will,
eventually, cross the mucous membranes of the upper respiratory
tract and enter the circulatory system. Thus the patient will be
administered nicotine but will become less accustomed to having the
immediate "rush" obtained from smoking. Thus, within the third
phase the patient has been weaned away from the need for the "rush"
of nicotine. The third phase is then used to continually reduce the
number of administrations needed and thereby reduce the amount of
nicotine administered. By this process the patient's dependency on
nicotine is slowly reduced and then eliminated thereby allowing the
patient to quit smoking.
When nicotine enters the circulatory system of a human patient it
is oxidized to cotinine within four to six hours. The present
invention includes the administration of cotinine and other
nicotine derivatives provided such derivatives do not result in
unacceptable adverse effects.
Indications
The method of the invention has applicability to smokers wishing to
quit or trying to quit who have experienced all or any of the
nicotine withdrawal symptoms associated with smoking cessation,
such as craving for nicotine, irritability, mood ability,
frustration or anger, anxiety, drowsiness, sleep disturbances,
impaired concentration, nervousness, restlessness, decreased heart
rate, increased appetite and weight gain.
While particularly applicable to smoking cessation, pulmonary
administration of nicotine could be of value for the treatment of
other diseases, such as for patients suffering from
neurodegenerative diseases, psychiatric disorders and other central
nervous system disorders responsive to nicotine receptor modulation
(see U.S. Pat. Nos. 5,187,169; 5,227,391; 5,272,155; 5,276,043;
5,278,176; 5,691,365; 5,885,998; 5,889,029; 5,914,328). Such
diseases include, but are not limited to, senile dementia of the
Alzheimer's type, Parkinson's disease, schizophrenia,
obsessive-compulsive behavior, Tourette's Syndrome, depression,
attention deficit disorder, myasthenia gravis and drug
addiction.
Formulations
Pharmaceutical grade nicotine can be produced as a colorless to
pale yellow liquid. The pure liquid could be aerosolized and
inhaled by itself. Alternatively, a formulation may include a
buffer to enhance absorption. Any absorption enhancers including
ammonia could be used with the formulation. However, a typical
formulation is only nicotine dissolved in water or dry powder
nicotine. Methods of formulating liquids and liquid inhalers are
disclosed in U.S. Pat. Nos. 5,364,838; 5,709,202; 5,497,763;
5,544,646; 5,718,222; 5,660,166; 5,823,178; and 5,910,301; all of
which are incorporated by reference to describe and disclose such.
Formulations of nicotine include aqueous formulations, aqueous
saline formulations, and ethanol formulations. All of these
formulations may be included with additional components such as
permeation enhancers, buffers, preservatives and excipient and
carrier components and additives normally included within
formulations for aerosolized drug delivery.
Nicotine is freely soluble in water. An aqueous nicotine solution
may be readily aerosolized and inhaled. The nicotine solution can
be placed in a low boiling point propellant in a pressurized
canister and released using a conventional metered dose inhaler
(MDI) device. Preferably, the MDI device is modified so that the
aerosolized dose is released each time at the same inspiratory flow
rate and inspiratory volume. When this is done the patient is more
likely to receive the same dose each time. A device for obtaining
repeating dosing with an MDI canister is taught in U.S. Pat. No.
5,404,871.
In accordance with the present invention it is preferable to load
the nicotine solution into a container which opens to a porous
membrane. When the formulation is forced through the membrane it is
aerosolized. Such a container is taught in U.S. Pat. No. 5,497,763
and is loaded into a device and delivered via a method as taught in
U.S. Pat. No. 5,823,178. Both patents are incorporated herein by
reference to describe and disclose containers, devices and methods
of drug delivery by inhalation.
A dry powder formulation comprising a pharmacologically acceptable
salt of nicotine alone or with additives such as components to
prevent the particles from sticking together may be used.
Supplemental Treatment Methodology
Smokers wishing to quit may be treated solely with respiratory
nicotine as indicated above, i.e. by intrapulmonary delivery.
However, it is possible to treat such patients with a combination
of pulmonary administration and other means of administration, such
as transdermal administration. Transdermal nicotine is preferably
administered to maintain a steady state level of nicotine within
the circulatory system. Nasal or buccal formulation could be used
for nasal or buccal delivery which could supplement aerosolized
delivery.
Based on the above, it will be understood by those skilled in the
art that a plurality of different treatments and means of
administration can be used to treat a single patient. For example,
a patient can be simultaneously treated with nicotine by
transdermal administration, nicotine via pulmonary administration,
in accordance with the present invention, and nicotine which is
administered to the mucosa.
The instant invention is shown and described herein in a manner
which is considered to be the most practical and preferred
embodiments. It is recognized, however, that departures may be made
therefrom which are within the scope of the invention and that
obvious modifications will occur to one skilled in the art upon
reading this disclosure.
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